This invention generally relates to polymeric microspheres for controlled release of ACTH.
Adrenocorticotropic hormone (ACTH) is a polypeptide secreted by the anterior pituitary gland. The polypeptide contains 39 amino acids and has a molecular weight of about 4500 Daltons. ACTH is extracted from the pituitary of mammals, especially pigs, for clinical use. The activity of ACTH is defined by a USP assay in hypophysectomized rats.
ACTH stimulates the adrenal cortex to synthesize and secrete adrenocortical hormones including cortisol, corticosterone, several weakly androgenic steroids, and, to a very limited extent, aldosterone. Under normal circumstances, endogenous release of ACTH is stimulated by corticotropin releasing factor (CRF) which is secreted by the hypothalamus. Exogenously administered ACTH produces all of the pharmacological effects usually produced by endogenous ACTH.
ACTH is utilized for its anti-inflammatory and immunosuppressant properties. In particular, it has been used for the following indications: 1) acute exacerbations of Multiple Sclerosis, 2) acute exacerbations of rheumatic disorders such as Rheumatoid Arthritis and Psoriatic Arthritis, 3) acute episodes of Ulcerative Colitis, 4) Infantile spasms and 5) acute bouts of Systemic Lupus Erythematous. Currently, for clinical purposes, ACTH is available as Corticotropin.TM. for injection, repository Corticotropin.TM. injection (containing partially hydrolyzed gelatin) and Corticotropin.TM. zinc hydroxide suspension.
Corticotropin injection is rapidly absorbed following IM or SQ injection, whereas after injection of corticotropin zinc hydroxide suspension or repository corticotropin injection, the drug is absorbed over a period of 4-10 hours, and plasma levels return to baseline after 24 hours.
ACTH is generally administered once or twice a day for up to 7-21 days, necessitating frequent IV or IM or SQ injections. The advantages of a controlled release formulation for ACTH include increased patient compliance and acceptance by reducing the number of injections, increased therapeutic benefit by eliminating the peak and valley changes in blood levels, and potentially lowering the total administered amount of drug by reducing peaks and valleys.
One means for controlling blood levels of a compound is to administer it in the form of a polymeric matrix that releases compound as a function of polymer degradation and/or drug diffusion. A variety of biodegradable and non-biodegradable polymers have been used for such applications, including polyesters such as poly(lactide-co-glycolide)s, polyanhydrides, polyorthoesters, and ethylenevinyl acetate polymers. In general, release is controlled by selection of the appropriate polymer, encapsulation conditions, and drug loading and excipients.
Examples of these polymeric systems are described in U.S. Pat. No. 4,891,225 to Langer and U.S. Pat. No. 4,906,474 to Langer (polyanhydrides), U.S. Pat. No. 4,391,797 to Folkman, et al., (ethylenevinyl acetate polymers), U.S. Pat. No. 4,767,628 to Hutchinson (polylactide, polylactide-co-glycolide acid), and U.S. Pat. No. 4,530,840 to Tice, et al. (polylactide, polyglycolide, and copolymers).
However, controlled release at the desired rate and over the desired period is difficult to achieve. Moreover, the conditions used to encapsulate the drug must not result in degradation of the drug to be delivered nor must the drug react with the polymeric matrix so as to inactivate or bind the drug. As important in a clinical situation, the delivery means must be cost effective to produce, stable to storage, and administrable using standard methodology.
It is therefore an object of the present invention to provide a method for making microspheres containing ACTH with very little loss of activity or material, and the resulting ACTH containing microspheres.
It is a further object of the present invention to provide a method for making microspheres formed from a broad range of polymers which contain active ACTH releasable in a controlled fashion, and the microspheres produced by such a process.